Liver homeostasis is maintained by midlobular zone 2 hepatocytes

Abstract

The liver is organized into zones in which hepatocytes express different metabolic enzymes. The cells most responsible for liver repopulation and regeneration remain undefined, because fate mapping has only been performed on a few hepatocyte subsets. Here, 14 murine fate-mapping strains were used to systematically compare distinct subsets of hepatocytes. During homeostasis, cells from both periportal zone 1 and pericentral zone 3 contracted in number, whereas cells from midlobular zone 2 expanded in number. Cells within zone 2, which are sheltered from common injuries, also contributed to regeneration after pericentral and periportal injuries. Repopulation from zone 2 was driven by the insulin-like growth factor binding protein 2–mechanistic target of rapamycin–cyclin D1 (IGFBP2-mTOR-CCND1) axis. Therefore, different regions of the lobule exhibit differences in their contribution to hepatocyte turnover, and zone 2 is an important source of new hepatocytes during homeostasis and regeneration.

Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis

“…However, several recent studies have presented evidence against this study and demonstrated that all hepatocytes have similar proliferative potential, regardless of their location [6,[9][10][11][12]. Furthermore, very recent two studies showed that zone 2 is the region J o u r n a l P r e -p r o o f with the highest homeostatic hepatocyte proliferation [13,14]. Therefore, the mechanism of liver regeneration, including repair responses to liver injury, is still a matter of debate.…”

“…Furthermore, the Cre ERT2 gene is knocked into the Axin2 locus in Axin2-Cre ERT2 mice [28], which causes heterozygous deletion of Axin2. Wei et al [13] showed that increased proliferation of pericentral hepatocytes previously reported by Wang et al [8] was caused by the heterozygous deletion of Axin2. However, DEN-induced HCC development was comparable with that in Axin2-Cre ERT2 and Cre ERT2 -negative control mice in the present study (Supplementary Figure 5), suggesting that the heterozygous deletion of Axin2 was unlikely to have affected liver tumorigenesis.…”

Polyploidy control in hepatic health and disease

“…More strikingly, CRADD/RAIDD appears to suppress liver regeneration emanating from zone 2 hepatocytes. This is suggested by the results from an elegant targeted transposon-based CRISPR loss-offunction, as well as trans-activation screen, using selected sgRNAs for genes preferentially expressed in zone 2 hepatocytes [20]. Together, these observations open up the possibility that breaking the ploidy barrier by chemical inhibition of the PIDDosome may promote liver regeneration in transplantation or other regenerative settings.…”

“…This effect, however, is equaled out with age and ploidy is rather equally distributed across the lobule in the adult human liver [17][18][19]. Studied in the mouse, homeostatic proliferation is most frequently observed in zone 2, as observed in inducible Ki67-Cre or Hamp2-Cre reporter mice [20,21]. In addition to zone 2, also diploid pericentral (zone 3) hepatocytes contribute to liver homeostasis [22] although the importance of this population is unclear [23].…”

“…Drug and diet induced liver injury primarily affect the periportal (zone 1) and pericentral (zone 3) hepatocyte populations (Figure 2). Two recent studies show that zone 2 hepatocytes can regenerate the liver upon such types of zonal injury as this hepatocyte population is shielded from the insult [20,21]. Upon partial hepatectomy, a type of injury that induces regeneration without a zonal bias, a wave-like propagation of proliferation from the periportal vein (zone 1) to the central vein (zone 3) can be detected [21,24].…”